DOACs may reduce thromboembolic events in patients with mitral stenosis and AF
Outcomes of Direct Oral Anticoagulants in Patients With Mitral Stenosis
Introduction and methods
Direct oral anticoagulants (DOACs) effectively reduce thromboembolic events in patients with AF, but AF patients with mitral stenosis or mechanic prosthetic heart valves have been excluded from trials [1-5], leaving warfarin as the only oral anticoagulant option for these patients. Mitral stenosis combined with AF increased risk of stroke >20 times, likely due to stasis in the left atrium . Efficacy of warfarin in patients with mitral stenosis and AF can be reduced by the poor quality of therapy (quality of international normalized ratio control measured by time in therapeutic range), especially in developing countries .
Therefore, it is interesting to investigate the efficacy of DOACs in patients with mitral stenosis and AF. DOACs are used in these patients as some physicians are unclear of the definition ‘nonvalvular AF’ and others prescribe DOACs off-label in patients with mitral stenosis.
This study analyzed data of 2230 patients with AF and mitral stenosis who were prescribed oral anticoagulation for >3 weeks between February 2008 and January 2017. Medical records from the Health Insurance Review and Assessment Service of the Republic of Korea database were reviewed and a case-control analysis was performed using data of patients with off-label use of DOACs and those with propensity score matched warfarin use (1:1 ratio). Patients with a history of mitral valve surgery were excluded.
Primary outcome was defined as the first hospitalization with a diagnosis of an ischemic stroke or systemic embolism after 3 weeks of DOAC use. Safety endpoint was intracranial hemorrhage. Mean follow-up was 27 months.
- There was a greater reduction in strokes or systemic embolisms the DOAC group (2.22%/year) than in the warfarin group (4.19%/year) (adjHR: 0.28; 95%CI: 0.18- 0.45, log-rank P<0.0001 for difference in cumulative incidence).
- Incidence of intracranial hemorrhages was nonsignificant between groups (DOAC group: 0.49%/year, warfarin group: 0.93%/year; adjHR: 0.53; 95% CI: 0.22 to 1.26).
- All-cause death was reduced in the DOAC group vs the warfarin group (3.45%/year vs 8.08%/year, adjHR:0.41; 95%CI:0.30-0.56, log-rank P<0.0001 for difference in cumulative incidence).
This study of insurance data showed that in patients with mitral stenosis and AF, use of DOACs resulted in reduced rates of thromboembolism compared to warfarin group, whereas DOACs and warfarin had similar efficacy in reducing hemorrhagic strokes. These findings justify randomized clinical trials to investigate the superiority of DOACs over warfarin in patients with mitral stenosis and AF.
Giugliano and O’Gara first explain why use of DOACs in patients with AF and mitral stenosis or mechanical heart valve replacement is not supported in guidelines or by regulatory authorities: these patients were excluded from trials because they are at very high risk for thromboembolism without the use of anticoagulation and in addition, a phase 2 trial of dabigatran was prematurely stopped because of harm.
After summarizing the results they say that ‘given the paucity of information regarding the use of DOACs in patients with MS, these observational data are welcome and should be viewed as hypothesis-generating’. They do think though that some of the HRs are too optimistic (72% reduction in thromboembolic events, 59% reduction in mortality) compared to those seen in other studies, which is most likely due to confounding. One of the limitations of this study is that most likely a high number of patients received subtherapeutic levels of warfarin therapy and those with mitral valve surgery were excluded making it difficult to extrapolate these findings to patient groups with high level of time-in-therapeutic range with VKA or those who had prior valve surgery.
They list some of the differences between an observational analysis of insurance data and a randomized controlled trial (inclusion criteria, reporting on outcomes), and ‘agree with the authors and others that the time has come to answer this question with an adequately powered RCT with significant implications for the health of vulnerable populations’.